EP0177080B1 - Verfahren zur Herstellung von 4-Hydroxycumarin-Derivaten - Google Patents

Verfahren zur Herstellung von 4-Hydroxycumarin-Derivaten Download PDF

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EP0177080B1
EP0177080B1 EP85201436A EP85201436A EP0177080B1 EP 0177080 B1 EP0177080 B1 EP 0177080B1 EP 85201436 A EP85201436 A EP 85201436A EP 85201436 A EP85201436 A EP 85201436A EP 0177080 B1 EP0177080 B1 EP 0177080B1
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EP0177080A1 (de
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Ian David Entwistle
Peter Boehm
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Shell Internationale Research Maatschappij BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
    • C07D311/56—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 without hydrogen atoms in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • This invention relates to a process for preparing certain 4-hydroxycoumarin derivatives.
  • US Patent No. 3,957,824 discloses a class of 4-hydroxycoumarin derivatives having anti-coagulant properties, which are useful as rodenticides, or in human medicine, of general formula wherein R 1 and R 2 are the same or different and are hydrogen or halogen atoms, preferably chlorine or bromine, or alkyl or alkoxy groups, preferably having up to 6 carbon atoms, R 3 is an aryl group having the formula where m is 1 or 2, and R is the same or different and is a halogen atom, a straight or branched chain alkyl or alkoxy group, preferably containing at least 2, more preferably from 5 to 12 carbon atoms, a cycloalkyl, preferably cyclohexyl group, an aralkyl, preferably a-aralkyl group, a phenyl or a phenoxy group, a halogeno, preferably para halogeno, substituted derivative
  • the halogen atom or atoms are preferably chlorine or bromine.
  • R is preferably in the para position and when m is 2 one of the R groups is preferably in the para position.
  • R 3 contains at least 1 but not more than 3 and optimally not more than 2 halogen atoms.
  • the above compounds of formula I are prepared by condensing 4-hydroxy coumarin (II) with compounds of general formula III without a solvent or in an organic solvent such as acetic acid in the presence of a dehydrating agent such as sulphuric acid or by condensing 4-hydroxy coumarin (II) with a compound of general formula IV with or without the use of a solvent.
  • R 1 , R 2 and R 3 have the meanings given previously and Hal is halogen, preferably chlorine or bromine.
  • Compounds of structure IV may be prepared from compounds of general structure III by treatment with reagents such as phosphorus tribromide, phosphorus trichloride or thionyl chloride in an inert solvent such as methylene chloride, chloroform or carbon tetrachloride.
  • reagents such as phosphorus tribromide, phosphorus trichloride or thionyl chloride in an inert solvent such as methylene chloride, chloroform or carbon tetrachloride.
  • condensation of such compounds of formulae II and III in acetic acid at 110°C.
  • condensation of compounds of formulae II and III is typically effected at 160 to 170°C.
  • Reaction of compound of formulae II and IV is typically at 130 to 140°C (for these latter temperature ranges see Shadbolt et al J. C. S. Perkin 1, (1976) No. 11, pages 1190 to 1195).
  • R 1 and R 2 are both hydrogen and R 3 is a 4-phenylphenyl group (difenacoum) and that wherein R 1 and R are both hydrogen and R 3 is a 4-(4-bromophenyl)phenyl group (brodifacoum).
  • GB-A-2 126 578, and the corresponding EP-A-98 629 discloses a further class of 4-hydroxycoumarin derivatives having anticoagulant properties, particularly as rodenticides.
  • these compounds have the formula in which Z represents a halogen atom, preferably a chlorine atom, and n is 0, 1 or 2 and R 4 represents either (1) a grouping which comprises a phenylene radical attached directly or indirectly to the tetralin ring and having in the para position (with respect to such attachment) an electron-withdrawing atom or group whose rotational volume substantially does not exceed that of a phenyl group and which forms together with said phenylene radical a polarisable structure, or (2) a grouping selected from: and or (3) a grouping which comprises a phenylene radical attached directly to the tetralin ring and having in the para position (with respect to such attachment) a substituted furanyl or thiophenyl radical attached thereto directly or through oxygen and/or m
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, alkyl of up to 6 carbon atoms and alkoxy of up to 6 carbon atoms
  • R 3 represents a group selected from where X represents a halogen atom or a group C 1-12 alkyl, C 1-12 alkoxy, C 3 - 8 cycloalkyl, CN, N0 2 , SO 2 R 5 , CF 3 , OCF 3 , COOR 5 or COR 5 , where R 5 is C 1-6 alkyl, n' is 0, 1 or 2 and Y is a fluorine or chlorine atom; where n' and Y are as defined above, X is as defined above or is hydrogen, n" is 0 or 1 and D is an oxygen atom or a group ⁇ O ⁇ (CH 2 ) m ⁇ , ⁇ (CH 2 ) m ⁇ O ⁇
  • L in formula VI is preferably OH, Br or Cl.
  • R 1 and R 2 are both hydrogen.
  • X is not hydrogen it preferably represents a fluorine, chlorine or bromine atom or a group CN, N0 2 , CF 3 or OCF 3 , more preferably a chlorine or bromine atom or a group CN or CF 3 .
  • the process of the invention is of most particular interest when applied to the preparation of difenacoum, bromdifacoum or 3-[3-(4-(4-trifluoromethylbenzyloxy)phenyl)-1,2,3,4-tetrahydro-1-naphthyl]-4-hydroxycoumarin.
  • the organic solvent may be formic acid or a mixture of formic acid and at least one C 2-6 aliphatic carboxvlic acid having a boiling temperature at atmospheric pressure in the range 60°C to 105°C. Mixtures of formic acid (boiling temperature 100.5°C) and glacial acetic acid (boiling temperature 118°C) having boiling temperatures in this range, particularly in volume proportions formic acid:acetic acid of about 3:1, are preferred.
  • the catalyst may conveniently be a mineral acid, such as sulphuric or, preferably, orthophosphoric acid; an acid salt, such as potassium hydrogen sulphate; a Lewis acid such as ferric chloride, zinc chloride or potassium chloride; or silica gel.
  • a mineral acid such as sulphuric or, preferably, orthophosphoric acid
  • an acid salt such as potassium hydrogen sulphate
  • a Lewis acid such as ferric chloride, zinc chloride or potassium chloride
  • silica gel silica gel.
  • Reaction temperatures in such solvent/catalyst systems are preferably in the range 70°C to reflux temperature, more preferably 80°C to reflux temperature.
  • the solvent is a liquid chlorinated alkane
  • the catalyst is a sulphonic acid
  • reaction is effected at a temperature in the range 60°C to the reflux temperature of the reaction mixture.
  • the chlorinated alkane is one which is liquid at ambient temperature, e.g. C 2 - 4 di- and trichloroalkanes.
  • chlorinated alkanes examples include 1,2-dichloroethane (b.p. 83°C to 84°C), 1,1,2-trichloroethane (b.p. 113°C to 114°C), 1,1,1-trichloroethane (b.p. 74°C to 75°C), 1,1-dichloropropane (b.p. 87°C), 1,2-dichloropropane (b.p. 95°C to 96°C) and 1,3-dichloropropane (b.p. 125°C).
  • 1,2-Dichloroethane, 1,1,2-trichloroethane and 1,3-dichloropropane have been found to be very suitable.
  • sulphonic acids include methanesulphonic acid, trifluoromethanesulphonic acid, and aryl sulphonic acids such as benzenesulphonic acid and p-toluenesulphonic acid.
  • the relative quantities of the reactants are not critical. However it is preferred for there to be 1 to 4 mols preferably 1 to 3 mols, of 4-hydroxycoumarin per mol of compound of formula VI, and, in the case of a sulphonic acid catalyst, for there to be 0.25 to 2 mols, preferably 0.5 to 1.5 mols, of sulphonic acid per mol of compound of formula VI.
  • pTSA p-toluenesulphonic acid
  • BSA benzenesulphonic acid
  • MSA methanesulphonic acid
  • DCE 1,2-dichloroethane (b.p. 83-84°C)
  • TCE 1,1,2-trichloroethane (b.p. 113-114°C)
  • DCP 1,3-dichloropropane (b.p. 125°C).
  • Example 15 The process of Example 15 was followed except that 1,1,2-trichloroethane (20 ml) was used in place of the 1,2-dichloroethane, and the reaction mixture was refluxed for 6 hours (not 24 hours). Brodifacoum (8.8g, 84%) mp 228-235°C was obtained.
  • Example 15 The process of Example 15 was followed except that 3-biphenyl-4-yl-1,2,3,4-tetrahydro-1-naphthol was used in place of the bromo compound, the resulting product being difenacoum, 3-(3-biphenyl-4-yl-1,2,3,4-tetrahydro-1-naphthyl)-4-hydroxycoumarin, mp 215-219°C, in 95% yield.
  • Example 16 The process modifications of Example 16 were applied to the process of Example 17. Difenacoum, mp 215-219°C, was obtained in 83% yield.
  • Example 17 The process of Example 17 was followed except that in place of the naphthol was employed 2-biphenyl-4-yl-1,2-dihydronaphthalene. Difenacoum, mp 215-219°C, was obtained in 76% yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrane Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Claims (12)

1. Verfahren zur Herstellung eines 4-Hydroxycumarinderivats der Formel
Figure imgb0035
worin R1 und R2 unabhängig voneinander aus der aus Wasserstoff, Halogen, Alkyl mit bis zu 6 Kohlenstoffatomen und Alkoxy mit bis zu 6 Kohlenstoffatomen bestehenden Gruppe ausgewählt sind und R3 eine Gruppe bedeutet, ausgewählt unter
Figure imgb0036
worin X ein Halogenatom oder eine C1-12Alkylgruppe, C1-12Alkoxygruppe, C3-8Cycloalkylgruppe, CN, N02, SO2R5, CF3, COOR5 oder CORs darstellt, worin R5 für C1-6Alkyl steht, n' den Wert 0, 1 oder 2 hat und Y ein Fluor- oder Chlolatom ist;
Figure imgb0037
worin n' und Y wie vorstehend definiert sind, X wie oben definiert ist oder Wasserstoff bedeutet, n" den Wert 0 oder 1 hat und D ein Sauerstoffatom oder eine Gruppe ―O―(CH2)m―. (CH2)m―O―, ―O―(CH2)m―O― ―(CH2)m ―O―(CH2)P,―(CH2)―m, oder―CH=CH―, oder ein Schwefelanalogon hievon, bedeutet, worin m im Bereich 1 bis 6 liegt und p im Bereich 1 bis 6 liegt;
Figure imgb0038
worin X, n' und Y wie oben unter (a) definiert sind; (d) einer Gruppe, ausgewählt unter
Figure imgb0039
und
Figure imgb0040
und (e) einer Gruppe, ausgewählt unter
Figure imgb0041
worin X und n" sie oben unter (b) definiert sind, A ein Sauerstoff- oder Schwefelatom ist und D' ein Sauerstoffatom oder eine -CH2-Gruppe darstellt, welches Verfahren ein Kondensieren von 4-Hydroxycumarin mit einer Verbindung der Formel
Figure imgb0042
oder dem entsprechenden 1,2-Dihydronaphthalin umfaßt, worin R1, R2 und R3 wie oben definiert sind un L ein Hydroxygruppe oder ein Halogenatom darstellt, in Anwesenheit eines organischen Lösungsmittels und eines Katalysators, dadurch gekennzeichnet, daß das Lösungsmittel unter Ameisensäure, einem Gemisch aus Ameisensäure und wenigstens einer C2-6 aliphatischen Carbonsäure mit einer Siedetemperatur bei Atmosphärendruck im bereich 60°C bis 105°C und einem flüssigen chlorierten Alkan mit einer Siedetemperatur im Bereich 60°C bis 125°C ausgewählt wird und daß die Umsetzung bei einer Temperatur im Bereich 60°C bis zur Rückflußtemperatur des Reaktionsgemisches vorgenommen wird.
2. Verfahren nach Anspruch 1, worin R1 und R2 jeweils Wasserstoff bedeuten.
3. Verfahren nach Anspruch 1 oder 2, worin X ein Fluor-, Chlor- oder Bromatom oder eine Gruppe CN, NO2, CF3 oder OCF3 bedeutet.
4. Verfahren nach Anspruch 3, worin X ein Chlor- oder Bromatom oder eine Gruppe CN oder CF3 bedeutet.
5. Verfahren nach Anspruch 1 oder 2, worin R3 eine Gruppe
Figure imgb0043
 darstellt, worin n', Y, n" und D wie in Anspruch 1 definiet sind und X Wasserstoff bedeutet oder wie in Anspruch 3 oder 4 definiert ist.
6. Verfahren nach Anspruch 5, worin R3 eine Gruppe
Figure imgb0044
darstellt, worin X, n', Y und n" wie in Anspruch 5 definiert sind und D ein Sauerstoffatom oder eine Gruppe ―O―CH2―, ―CH2―CH2―, ―CH2―CH2―CH2― oder -CH=CH- bedeutet.
7. Verfahren nach Anspruch 6, worin n den Wert 0 hat, n" den Wert 0 oder 1 hat, D ein Sauerstoffatom oder ein Gruppe ―O―CH2― darstellt und X für eine Gruppe CF3, H, CN oder Br steht.
8. Verfahren nach einem der Ansprüche 1 bis 7, worin das Lösungsmittel ein flüssiges chloriertes Alkan ist, der Katalysator ein Sulfonsäure ist und die Umsetzung bei einer Temperatur im Bereich von 60°C bis zur Rückflußtemperatur des Reaktionsgemisches ausgeführt wird.
9. Verfahren nach Anspruch 8, worin das flüssige chlorierte Alkan unter C2-4Di- und Trichloralkanen ausgewählt wird.
10. Verfahren nach Anspruch 9, worin das flüssige chlorierte Alkan unter 1,2-Dichlorethan, 1,1,2-Trichlorethan und 1,3-Dichlorpropan ausgewählt wird.
11. Verfahren nach einem der Ansprüche 1 bis 10, worin der Katalysator unter Methansulfonsäure, Benzosulfonsäure und p-Toluolsulfonsäure ausgewählt wird.
EP85201436A 1984-09-26 1985-09-10 Verfahren zur Herstellung von 4-Hydroxycumarin-Derivaten Expired EP0177080B1 (de)

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AT85201436T ATE38669T1 (de) 1984-09-26 1985-09-10 Verfahren zur herstellung von 4-hydroxycumarinderivaten.

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GB848424317A GB8424317D0 (en) 1984-09-26 1984-09-26 4-hydroxycourmarin derivatives
GB8424317 1984-09-26

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JP (2) JPH0794449B2 (de)
KR (1) KR930009794B1 (de)
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GB8424317D0 (en) * 1984-09-26 1984-10-31 Shell Int Research 4-hydroxycourmarin derivatives
GB9324517D0 (en) * 1993-11-30 1994-01-19 Octel Chem Ltd Process for the preparation of substituted 4-hydroxycoumarins

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GB1458670A (en) * 1973-05-23 1976-12-15 Ward Blenkinsop & Co Ltd Anti coagulant 3-tetrahydronaphthyl-4-hydroxy-coumarin deri vatives
EP0098629B1 (de) * 1982-06-14 1987-08-26 Shell Internationale Researchmaatschappij B.V. Anti-Koagulierungsmittel des 4-Hydroxycumarintyps, deren Zubereitung und diese enthaltende Ratten vernichtende Zusammenstellungen
GB8424317D0 (en) * 1984-09-26 1984-10-31 Shell Int Research 4-hydroxycourmarin derivatives

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EG17061A (en) 1993-02-28
JPH0770103A (ja) 1995-03-14
GR852319B (de) 1986-01-24
DK433385A (da) 1986-03-27
GB8424317D0 (en) 1984-10-31
ATE38669T1 (de) 1988-12-15
IL76490A (en) 1989-07-31
AU583533B2 (en) 1989-05-04
FI86718B (fi) 1992-06-30
EP0177080A1 (de) 1986-04-09
SU1358785A3 (ru) 1987-12-07
DK433385D0 (da) 1985-09-24
PT81183B (pt) 1987-09-30
NO853748L (no) 1986-04-01
ZW16985A1 (en) 1985-12-18
IE852354L (en) 1986-03-24
KR930009794B1 (ko) 1993-10-11
HU196982B (en) 1989-02-28
IN166513B (de) 1990-05-19
PT81183A (en) 1985-10-01
HUT40097A (en) 1986-11-28
KR860002491A (ko) 1986-04-26
NO169772B (no) 1992-04-27
ES547237A0 (es) 1986-03-01
JPH0794449B2 (ja) 1995-10-11
DK162993C (da) 1992-06-01
DE3566258D1 (en) 1988-12-22
DK162993B (da) 1992-01-06
NO169772C (no) 1992-08-05
CA1263396A (en) 1989-11-28
FI853662L (fi) 1986-03-27
PH22719A (en) 1988-11-28
FI86718C (fi) 1992-10-12
ES8604920A1 (es) 1986-03-01
ZA857326B (en) 1986-07-30
ZM6985A1 (en) 1986-01-23
AU4782285A (en) 1986-04-10
FI853662A0 (fi) 1985-09-24
IE58616B1 (en) 1993-10-20
BR8504673A (pt) 1986-07-15
JPS6185377A (ja) 1986-04-30
MA20532A1 (fr) 1986-04-01
IL76490A0 (en) 1986-01-31
OA08104A (en) 1987-03-31
NZ213591A (en) 1988-02-29
JP2602783B2 (ja) 1997-04-23

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